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(Circulation Research. 1996;79:415-423.)
© 1996 American Heart Association, Inc.

Articles

PD 81,723, an Allosteric Enhancer of the A₁ Adenosine Receptor, Lowers the Threshold for Ischemic Preconditioning in Dogs

Tsuneo Mizumura, John A. Auchampach, Joel Linden, Robert F. Bruns, Garrett J. Gross

the Department of Pharmacology and Toxicology (T.M., G.J.G.), Medical College of Wisconsin, Milwaukee; the Department of Internal Medicine and Molecular Physiology and Biological Physics (J.A.A., J.L.), University of Virginia, Charlottesville; and Central Nervous System Pharmacology Research (R.F.B.), Lilly Research Laboratories, Eli Lilly and Co, Indianapolis, Ind.

Correspondence to Garrett J. Gross, PhD, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226.

PD 81,723 (PD) acts allosterically to increase agonist binding to A₁ adenosine receptors and to enhance functional A₁ receptor–mediated responses in the heart and other tissues. To determine if PD lowers the threshold for ischemic preconditioning (PC), pentobarbital-anesthetized dogs were subjected to 60 minutes of left anterior descending coronary artery (LAD) occlusion and 3 hours of reperfusion. Ischemic PC was produced by either 2.5 or 5 minutes of LAD occlusion 10 minutes before the 60-minute occlusion. PD (100 µg/kg total dose, 5 to 50 µmol/L in coronary arterial blood) or vehicle was infused intracoronarily for 17.5 minutes before the 60-minute occlusion period in non-PC dogs or in dogs preconditioned with 2.5 minutes of ischemia. Myocardial infarct size was determined by triphenyltetrazolium staining and expressed as a percentage of the area at risk. Compared with the control group (26.3±3.6%, mean±SEM), infarct size was not significantly affected by 2.5 minutes of PC alone (23.4±4.2%) or by PD alone (26.5±1.7%) but was decreased by PD+PC (14.6±1.7%, P<.05) or by a longer period (5 minutes) of PC alone (12.5±3.3%). The intravenous administration of the selective antagonist of A₁ adenosine receptors, 8-cyclopentyl-1,3-dipropylxanthine (1 mg/kg), or the ATP-sensitive K⁺ channel blocker, glibenclamide (0.3 mg/kg), for 15 minutes before PD+PC blocked the protection (23.6±2.3% or 25.9±3.3%, respectively). None of the compounds studied affected systemic hemodynamics, collateral blood flow, or AAR. To determine which subtypes of canine adenosine receptors were affected by 10 µmol/L PD, radioligand binding studies were conducted using membranes derived from COS-7 cells expressing recombinant canine receptors and agonist radioligands. PD enhanced the binding of [¹²⁵I]N⁶-4-amino-3-iodobenzyladenosine (¹²⁵I-ABA) to A₁ receptors by increasing the t_1/2 for dissociation by 2.18-fold, but PD had no effect on the dissociation kinetics of ¹²⁵I-ABA from A₃ receptors or [¹²⁵I]-[2-(4-amino-3-iodo-phenyl)ethylamino]adenosine from A_2A receptors. Glibenclamide at concentrations up to 10 µmol/L had no effect on the binding of radioligands to recombinant canine A₁, A_2A, or A₃ receptors. These data suggest that PD reduces the amount of time required for ischemia to produce preconditioning by enhancing adenosine binding to its A₁ receptor. Glibenclamide prevents the protection afforded by A₁ receptor activation by a mechanism not involving adenosine receptor blockade.

Key Words: ischemic preconditioning • adenosine receptors • ATP-sensitive K⁺ channels • allosteric enhancers • glibenclamide

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